Pharmaceutical water systems are critical in parenteral aseptic manufacturing processes because of their influence on final product quality. Water of pharmaceutical quality is mainly used as a part of the product in formulation processes and as a cleaning agent for vessels and accessories in direct contact with the product, so it must strictly fulfill chemical and microbiological specifications established in internationally recognized monographies such as the United States Pharmacopeia (USP) and the European Pharmacopeia (EP) (1, 2). Pharmaceutical water installations must adhere to technical design criteria, most of which are included in guidelines (3). After several years, those installations may require renovation according to current exigencies and the latest technological advances.

Qualification by stages, from installation design to performance, and incorporating periodical monitoring of key variables at a less-intense frequency than performance qualification contribute greatly to the establishment of water system reliability under the concept of lifetime validation cycle given by USP (4). Nevertheless, daily practice shows that even with validated installations, these systems are not exempt from eventual deviations of their daily normal operation. Risk analysis (RA) methods are usually applied for studying these situations because they illustrate those limitations to which an installation can be subjected concerning failures and facilitate elimination or mitigation of their consequences with anticipated actions.

RA methods have been used in several industrial applications for some time (5). Recently, they have taken on special significance in pharmaceutical manufacturing processes (6, 7). The diversity of methods takes into account model adaptability to characteristics and peculiarities of the analyzed process. In particular, fault tree analysis (FTA) and failure modes and effects analysis (FMEA) have proven their effectiveness in installation analysis.

The present study describes an RA-based approach applied to a pharmaceutical water system, specifically to the water pretreatment and purification (WPP) process. The approach helped determine cause-and-effect complex interrelations in possible fault events through the FTA method, while equipments and components' criticality as well as their failure incidence level on this and other dependent processes was shown using FMEA. An action plan was also obtained that facilitated priorities assignment to improve the installation technically and operationally. In addition, effectiveness of actions was verified during a 15-day system revalidation period.

Process description and considerations

Figure 1 (FIGURE IS COURTESY OF THE AUTHORS)

The WPP process in this study matches the traditional arrangement for this kind of installation (see Figure 1). A first stage of sodium hypochlorite dosage was conceived originally to compensate possible deficits of free chlorine in the tap water supply, thus avoiding bioburden increase throughout the system.

In the coarse-particles removal stage, a Silex fixed bed was originally installed as filtration media, which was the same as the free-chlorine removal stage with a carbon–Silex mixed bed. Independent of their effectiveness, both devices generated inner flow patterns with a high probability of dead-zones formation, which are susceptible to microbiological growth. In addition, fixed-bed recipients constructed of strengthened polyester, softened water-storage tanks made of low-density polyethylene, and pipes and fittings made of poly(vinyl chloride) do not favor system cleaning and disinfection, thereby restricting the process to the use of chemical agents only. Hence the system is obviously far away from fulfilling sanitary requirements, where keeping free chlorine at suitable levels and constant water recirculation to prevent stagnation are the only means to avoid bioburden increments over the amount incorporated by tap-water supplies.

The purification stage, which carries the biggest weight in obtaining water of pharmaceutical quality, was originally designed as a two-stage reverse osmosis (RO) system based on polyamide membranes. Therefore, the previous free-chlorine removal stage is vital to prevent membrane deterioration by oxidation. A sodium hydroxide (NaOH) solution dosage system was incorporated later to ensure a lowering of carbon dioxide content in the pretreated water by converting and eliminating it as bicarbonates through the first-stage rejection stream, thus avoiding electrical conductivity (EC) out of limits (OOL) at the second-stage water product outlet.